Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2.

Metabotropic glutamate 2 receptors (mGlu) are involved in the pathogenesis of several CNS disorders and neurodegenerative diseases. Pharmacological modulation of this target represents a potential disease-modifying approach for the treatment of substance abuse, depression, schizophrenia, and dementias. While quantification of mGlu receptors in the living brain by positron emission tomography (PET) would help us better understand signaling pathways relevant to these conditions, few successful examples have been demonstrated to image mGlu in vivo, and a suitable PET tracer is yet to be identified. Herein we report the design and synthesis of a radiolabeled negative allosteric modulator (NAM) for mGlu PET tracer development based on a quinoline 2-carboxamide scaffold. The most promising candidate, 7-((2,5-dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[C]methoxyphenyl) quinoline-2-carboxamide ([C]QCA) was prepared in 13% radiochemical yield (non-decay-corrected at the end of synthesis) with >99% radiochemical purity and >74 GBq/μmol (2 Ci/μmol) specific activity. While the tracer showed limited brain uptake (0.3 SUV), probably attributable to effects on PgP/Bcrp efflux pump, in vitro autoradiography studies demonstrated heterogeneous brain distribution and specific binding. Thus, [C]QCA is a chemical probe that provides the basis for the development of a new generation mGlu PET tracers.